Fibrosis is an intrinsic response to chronic injury, maintaining organ integrity when extensive necrosis or apoptosis occurs. With protracted damage, fibrosis can progress toward excessive scarring and organ failure, as in liver cirrhosis.
Liver fibrosis is the common scarring reaction associated with chronic liver injury that results from prolonged parenchymal cell injury and/or inflammation. The fibrogenic response is characterized by progressive accumulation of extracellular matrix components enriched in fibrillar collagens and a failure of matrix turnover. This process is driven by a heterogenous population of hepatic myofibroblasts that mainly derive from hepatic stellate cells and portal fibroblasts. Hepatic stellate cells are liver-specific mesenchymal cells that play vital roles in liver physiology and fibrogenesis. They are located in the space of Disse and maintain close interactions with sinusoidal endothelial cells and hepatic epithelial cells. It is becoming increasingly clear that hepatic stellate cells have a profound impact on the differentiation, proliferation, and morphogenesis of other hepatic cell types during liver development and regeneration.
Some studies suggest that regression of fibrosis can be achieved by the successful control of the cause of the chronic liver injury, owing to termination of the fibrogenic reaction following clearance of hepatic myofibroblasts and restoration of fibrolytic pathways, such as during anti viral therapy targeting hepatitis B and C viruses.
While mild fibrosis remains largely asymptomatic, its progression toward cirrhosis, i.e., replacement of functional parenchyma by scar tissue accompanied by severe architectural and vascular distortion, is the major cause of liver-related morbidity and mortality. Moreover, numerous patients present initially in the clinic with advanced fibrosis or cirrhosis, which are largely irreversible. Therefore, antifibrotics that prevent progression toward cirrhosis or induce regression of fibrosis and cirrhosis are urgently needed.
Idiopathic pulmonary fibrosis (IPF) is a progressively fibrotic interstitial lung disease that is associated with a median survival of 2-3 years from initial diagnosis. Specifically, IPF is no longer thought to be a predominantly pro-inflammatory disorder. Rather, the fibrosis in IPF is increasingly understood to be the result of a fibroproliferative and aberrant wound healing cascade.
In addition, fibrosis of any other organ including heart, muscle, kidneys, pancreas, bowel, and others is the final common pathway for many disorders—many of which do not necessarily involve the immune system in their pathogenesis.
While some drugs effective against other known causes of fibrosis, such as chronic viral hepatitis B or C, autoimmune and biliary diseases, alcoholic steatohepatitis (ASH) or nonalcoholic steatohepatitis (NASH) may exert some anti fibrotic effect, most of them are more effective in preventing the deterioration of the process rather than actually reversing an existing fibrotic state. Moreover, for many of the liver disorders, as well as other organs, the exact cause of the disease is unknown, and therefore there are not targets for therapy. For these cases, a direct anti fibrotic compound is required.
Understanding of the complex network underlying liver fibrogenesis has allowed the identification of a large number of antifibrotic targets, but no antifibrotic drug has as-yet been approved. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development. Preclinical research has yielded numerous targets for antifibrotic agents, some of which have entered early-phase clinical studies, but progress has been hampered due to the relative lack of sensitive and specific biomarkers to measure fibrosis progression or reversal.
Whilst it may be expected that known anti-inflammatory drugs would by course also reduce fibrosis in a target organ, such anti-inflammatory drugs have not proven effective in this disease.
Many anti-inflammatory agents failed in alleviating fibrosis, suggest that additional pathways, some that are not yet identified, are involved in the process.
We hypothesise that the molecular pathways that lead to fibrosis are of higher complexity than originally anticipated and separate from those pathways which are related to inflammation in the relevant organ. Also in some organs, activation of inflammatory pathways may only one of many building blocks in the process of inducing fibrosis, and therefore, an anti-inflammatory compound is not sufficient for stopping the process.